Discovery of Polymyxin-based Antibacterial Agents Active Against Multi-Drug Resis

发现具有多药耐药性的多粘菌素类抗菌剂

• 批准号: 8465802
• 负责人: Matthew A Cooper
• 金额: $ 12.03万
• 依托单位: UNIVERSITY OF QUEENSLAND
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-04 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465802
• 关键词: Acinetobacter; Acinetobacter baumannii; Affinity; Anti-Bacterial Agents; Antibiotics; Area; Bacteria; Binding; Biological Assay; Carbapenems; Cells; Clinical; Colistin; Confocal Microscopy; Data; Development; Drug Kinetics; Drug effect disorder; Drug resistance; Drug-sensitive; Effectiveness; Electrons; Escherichia coli; Evaluation; Fosfomycin; Future; Gram-Negative Bacteria; Health; Health Care Costs; Healthcare Systems; Human; Image; In Vitro; Infection; Investigation; Kidney; Klebsiella pneumonia bacterium; Lactamase; Lactams; Lead; Life; Lipid A; Membrane; Methods; Molecular Target; Multi-Drug Resistance; Nuclear Magnetic Resonance; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Polymyxin Resistance; Polymyxins; Pseudomonas aeruginosa; Public Health; Publishing; Reporting; Research; Resistance; Resolution; Resort; Safety; Scanning; Structure; Structure-Activity Relationship; Surface Plasmon Resonance; Testing; Toxic effect; Transmission Electron Microscopy; Work; analog; base; carbapenem resistance; dosage; drug candidate; drug development; drug resistant bacteria; improved; in vivo; kidney cell; killings; nephrotoxicity; novel; pathogenic bacteria; pre-clinical; preclinical study; programs; rapid technique; research clinical testing; resistance mechanism; resistant strain; screening; tigecycline; tool

DESCRIPTION (provided by applicant): The emergence of multi-drug resistant pathogenic bacteria represents a serious and growing threat to human lives and national healthcare systems. These 'supebugs' now kill 100,000's of people each year and are estimated to add $20bn in healthcare costs in the US. In particular, the expansion of Gram-negative strains such as Klebsiella pneumonia, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa and the rapidly spreading NDM-1 phenotypes are of grave concern. For many of these Gram-negative infections, colistin (polymyxin E) remains the only option of 'last resort', where the carbapenems are no longer active, and cases of tigecycline resistance have been reported. Aims & Objectives: We aim to produce new antibiotics, based on colistin, that are active against resistant 'super-bugs' and that have better safety profiles than current 'last-resor' antibiotics. The research will deliver novel drug-candidates targeted at resistant pathogenic bacteria, and will also provide a detailed scientific understanding of the origins and mechanisms of antibiotic-induced kidney toxicity (nephrotoxicity).We will develop a detailed understanding of how colistin works to kill bacteria. In the longer term, the assays developed for profiling of nephrotoxicity will prove valuable in all areas of drug research, thus providing tools for both antibiotic-renal and more general drug-renal toxicity screening. The new colistin derivatives will be active against the serious Gram-negative super superbugs and attack both drug-sensitive and drug-resistant strains of the bacteria. Approach & methods: This program will use a world first synthetic method for the rapid synthesis of 1,400 colistin analogs for an unprecedented systematic investigation of structure-activity and structure- toxicity relationships. These novel compounds will be optimized for activity against drug-resistant Gram-negative bacteria, in particular NDM-1 strains, and then evaluated for mode of action, stability, cell toxicity and nephrotoxicity. They will also be profiled for binding to the bacterial membranes and molecular target (Lipid A). This will lead to in vivo proof-of-principle for drug action and pharmacokinetic studies for the selection of compounds for future pre-clinical evaluation.

描述（由申请人提供）：多重耐药致病菌的出现对人类生命和国家医疗保健系统构成了严重且日益严重的威胁。这些“超级细菌”现在每年杀死10万人，估计在美国增加200亿美元的医疗费用。特别是，革兰氏阴性菌株如肺炎克雷伯氏菌、大肠杆菌、鲍曼不动杆菌和铜绿假单胞菌的扩增以及快速传播的NDM-1表型令人严重关切。对于许多革兰氏阴性菌感染，粘菌素（多粘菌素E）仍然是“最后手段”的唯一选择，其中碳青霉烯类不再具有活性，并且已报告了替加环素耐药病例。宗旨和目标：我们的目标是生产基于粘菌素的新抗生素，这些抗生素对耐药的“超级细菌”具有活性，并且比目前的“最后一种”抗生素具有更好的安全性。该研究将提供针对耐药致病菌的新型候选药物，并将提供对抗生素诱导的肾毒性（肾毒性）的起源和机制的详细科学理解。我们将详细了解粘菌素如何杀死细菌。从长远来看，为分析肾毒性而开发的检测方法将证明在药物研究的所有领域都有价值，从而为药物肾毒性和更一般的药物肾毒性筛查提供工具。新的粘菌素衍生物将对严重的革兰氏阴性超级细菌具有活性，并攻击细菌的药物敏感和耐药菌株。途径和方法：该计划将使用世界上第一种合成方法快速合成1，400种粘菌素类似物，以进行前所未有的结构-活性和结构-毒性关系的系统研究。这些新化合物将针对针对耐药性革兰氏阴性细菌（特别是NDM-1菌株）的活性进行优化，然后评估作用模式、稳定性、细胞毒性和肾毒性。还将分析它们与细菌膜和分子靶标（脂质A）的结合情况。这将导致药物作用的体内原理验证和药代动力学研究，以选择化合物用于未来的临床前评价。

项目成果

Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B.

• DOI: 10.1021/acs.jmedchem.5b01593
• 发表时间: 2016-02-11
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Gallardo-Godoy A;Muldoon C;Becker B;Elliott AG;Lash LH;Huang JX;Butler MS;Pelingon R;Kavanagh AM;Ramu S;Phetsang W;Blaskovich MA;Cooper MA
• 通讯作者: Cooper MA

Can octapeptin antibiotics combat extensively drug-resistant (XDR) bacteria?

• DOI: 10.1080/14787210.2018.1483240
• 发表时间: 2018-06
• 期刊: Expert review of anti-infective therapy
• 影响因子: 5.7
• 作者: Blaskovich MAT;Pitt ME;Elliott AG;Cooper MA
• 通讯作者: Cooper MA

Evaluation of biomarkers for in vitro prediction of drug-induced nephrotoxicity: comparison of HK-2, immortalized human proximal tubule epithelial, and primary cultures of human proximal tubular cells.

• DOI: 10.1002/prp2.148
• 发表时间: 2015-06
• 期刊: PHARMACOLOGY RESEARCH & PERSPECTIVES
• 影响因子: 2.6
• 作者: Huang, Johnny X;Kaeslin, Geraldine;Ranall, Max V;Blaskovich, Mark A;Becker, Bernd;Butler, Mark S;Little, Melissa H;Lash, Lawrence H;Cooper, Matthew A
• 通讯作者: Cooper, Matthew A

Octapeptin C4 and polymyxin resistance occur via distinct pathways in an epidemic XDR Klebsiella pneumoniae ST258 isolate.

在流行性 XDR 肺炎克雷伯菌 ST258 分离株中，八肽素 C4 和多粘菌素耐药性通过不同的途径发生。

• DOI: 10.1093/jac/dky458
• 发表时间: 2019
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Pitt,MirandaE;Cao,MinhDuc;Butler,MarkS;Ramu,Soumya;Ganesamoorthy,Devika;Blaskovich,MarkAT;Coin,LachlanJM;Cooper,MatthewA
• 通讯作者: Cooper,MatthewA